Potential Impact of Accelerating the Primary Dose of Pneumococcal Conjugate Vaccine in Infants

Abstract

Objective

To estimate the potential effect of the acceleration of administration of the first dose of pneumococcal conjugate vaccine from 2 months to 6 weeks of age.

Design

Prediction model using data from a retrospective cohort study.

Setting

Published data from 8 states that participated in Active Bacterial Core Surveillance of the Emerging Infections Program Network for pneumococcus prior to pneumococcal conjugate vaccine introduction (July 1,1997- June 30, 2000).

Participants

A total of 759,739 live births under surveillance

Intervention

Estimating potential benefit of administration of the first dose of the pneumococcal conjugate vaccine at 6 weeks of age instead of 2 months of age.

Outcome Measures

Estimation of reduction in the rate of invasive pneumococcal disease in infants 61–90 days of age.

Results

The estimated direct effect of the acceleration of administration of the first dose of pneumococcal conjugate vaccine from 2 months to 6 weeks of age when this vaccine was first introduced could have reduced the burden of invasive pneumococcal disease in infants 61– 90 days of age by 39.9%, 56.0% and 72.1% for respective vaccine efficacies of 50%, 70% and 90%. This translates into preventing an estimated 73, 103, and 133 cases of invasive pneumococcal disease per year among approximately 4,112,052 live births in the United States.

Conclusion

The acceleration of administration of the pneumococcal conjugate vaccine from 2 months to 6 weeks of age could reduce the burden of invasive pneumococcal disease among infants. This observation may be important when a new conjugate vaccine becomes available, particularly among populations with prevalent invasive pneumococcal disease from a serotype included in the new vaccine.

Streptococcus pneumoniae is a leading cause of invasive bacterial disease in children, including pneumonia, meningitis, and bacteremia. Since the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, rates of invasive pneumococcal disease (IPD) in children have decreased significantly. More recently, several studies have reported increasing IPD rates due to non-PCV7 serotypes.^1–8

The Advisory Committee on Immunization Practices (ACIP) has recommended administering four doses of PCV7 to infants at 2, 4, 6 and 12 to 15 months of age, respectively.⁹ One retrospective cohort study in two U.S. urban communities noted that the median age of administration for the first three PCV7 doses in that study population was 64, 129, and 193 days of age, respectively.¹⁰ The National Immunization Survey has estimated that in 2006–2007, 80% of children received 1 or more doses of PCV7 by 3 months of age.¹¹

Since the introduction of PCV7, the reduction in IPD in the U.S. has been significant even in non-vaccinated populations. Indeed, evidence of indirect protection among adults and infants too young to receive PCV7 has been observed.^12–14 However, neonates and young infants are at high risk for developing invasive bacterial infections due to several organisms, including S. pneumoniae. Given that ACIP recommendations for PCV7 permit administering the first dose as early as 6 weeks of age, the objective of our study was to estimate the potential effect on IPD rates in young infants if the time of administration of the first pneumococcal conjugate vaccine dose was accelerated from 2 months to 6 weeks of age. A significant decline in IPD rates resulting from earlier first dose administration would be an important consideration when a new conjugate vaccine becomes available—before the onset of indirect protection, especially in geographic areas with high rates of IPD.

Methods

Because of indirect effects on IPD rates that began within a year of PCV7 introduction, it is difficult to estimate the direct effect of early first dose administration through the use of data collected after the introduction of PCV7. Thus, in this study we used pre-PCV7 data on IPD rates for our calculations. To estimate the IPD rates in young infants, we used published numbers of pneumococcal infections by month of age for infants <90 days of age from July 1, 1997 through June 39, 2000.¹² The IPD rate equaled the number of laboratory-confirmed cases of IPD divided by the number of live births (N=759,739) in the 8 surveillance areas during the 3 pre-PCV7 years.¹⁵

To estimate the national coverage for the first dose of PCV7, we used the 2006–2007 National Immunization Survey, which estimated that 80% of children in the U.S. received 1 or more doses of PCV7 by 3 months of age.¹¹ To estimate overall vaccine efficacy, we used published estimates of PCV7 vaccine efficacy from several recent studies which ranged from 46% to 89%.^16–18 On the basis of this data, we assumed vaccine efficacy of 50%, 70%, and 90%.

Assuming a two-week delay in the direct immune response of an accelerated first dose of pneumococcal conjugate vaccine administered at 6 weeks of age, the benefit would be seen among infants beginning at 2 months of age. To estimate the potential direct effect on IPD rates of the acceleration of the administration of the first pneumococcal conjugate vaccine dose from 2 months to 6 weeks of age, we multiplied the IPD rate for infants 61–90 days of age (4.48 per 100,000)¹² by the percent not vaccinated (20%) and added that to the product of the IPD rate multiplied by 1 minus the vaccine efficacy multiplied by the percent vaccinated (80%). The projected rate reduction equaled the pre-PCV7 IPD rate minus the projected IPD rate after acceleration to 6 weeks (Table 1). To estimate the number of cases prevented by acceleration of the first pneumococcal conjugate vaccine dose, we multiplied the projected rate reduction by the number of live births in the U.S. according to the 2004 United States Census (4,112,050 births)¹⁵, divided by 100,000. The number needed to be vaccinated at 6 weeks equaled the inverse of the projected rate reduction times 100,000. The 95% confidence intervals were computed using the Poisson distribution.^19,20

Table.

Projected effect of accelerating the first dose of PCV7 from 2 months to 6 weeks of age on IPD cases per 100,000 infants aged 61 to 90 days

IPD rate in 1997 – 2000	Vaccine Efficacy, %	Projected IPD rateb	Projected Rate Reduction	Projected No. of US Cases Preventedc (95% CI)	NNTd (95% CI)
Effect assuming 3 Vaccine Efficacies
4.48 a	50%	2.69	1.79	74 (58–93)	55,866 (55,404–56,331)
	70%	1.97	2.51	103 (84–125)	39,841 (39,451–40,234)
	90%	1.25	3.23	133 (111–158)	30,960 (30,616–31,307)
Effect assuming 50% lower IPD rate
2.24	50%	1.34	0.90	37 (26–52)	111,111 (110,459–111,766)
	70%	0.99	1.25	51 (38–67)	80,000 (79,447–80,556)
	90%	0.63	1.61	66 (51–84)	62,112 (61,624–62,602)
Effect assuming 50% higher IPD rate
6.72	50%	4.03	2.69	111 (91–134)	37,175 (36,798–37,555)
	70%	2.96	3.76	155 (132–181)	26,596 (26,277–26,918)
	90%	1.88	4.84	199 (172–229)	20,661 (20,380–20,945)

^aThe IPD rate in 61–90 day old infants, using 1997–2000 data (before PCV7 introduction).¹¹

^bProjected IPD rate in 61–90 day old infants if first dose of PCV7 is administered at 6 weeks instead of 2 months = (((IPD rate 1997 to 2000) × (0.2))+(( IPD rate 1997 to 2000) × (1 - VE) × (0.8))).

^cEstimated annual number of cases prevented in the U.S. using 2004 Census data of 4,112,050 live births.

^dNumber needed to vaccinate to prevent 1 case of IPD in the U.S. equals (1/projected rate reduction) X 100,000.

Results

The projected rates of IPD in infants 61–90 days of age who would receive the first dose of pneumococcal conjugate vaccine at 6 weeks of age would be 2.69, 1.97, and 1.25 cases per 100,000 infants with respective vaccine efficacies of 50%, 70%, and 90% (Table). These respective estimates translated into absolute risk reductions of 1.79, 2.51, and 3.23 cases per 100,000 infants. These respective projections correspond to 39%, 56%, and 72% reductions in IPD rates, and 74, 103, and 133 cases of IPD prevented annually among infants 61–90 days of age in the U.S. The number of infants needed to be vaccinated at 6 weeks of age to prevent one case of IPD would be 55,866, 39,841, and 30,960 infants with respective vaccine efficacies of 50%, 70% and 90%.

To account for annual and regional variation in IPD rates, we calculated the same estimates using a 50% lower and 50% higher baseline rate of IPD (Table). When we used a 50% lower IPD rate in infants 61–90 days of age, the number of cases prevented was halved and the number of infants needed to be vaccinated at 6 weeks was doubled. When we used a 50% higher IPD rate, the number of cases prevented doubled and the number of infants needed to be vaccinated at 6 weeks to prevent one case was halved.

Comment

Vaccination is considered one of the great public health achievements of the 20^th century and contributed to the 99.7% decrease in childhood mortality from major infectious diseases between 1900 and 1998.^21,22 Most efforts to improve childhood protection focus on increasing vaccination rates or developing new or better vaccines. In this study, we evaluated the potential impact of the acceleration of the administration of the first dose of PCV7 from 2 months to 6 weeks of age. We estimated that this change could have prevented 73 to 133 cases of IPD among infants 61–90 days of age when PCV7 was introduced. Because meningitis accounted for 15% of all IPD in young infants both before and after PCV7 introduction,²³ we would anticipate that 15% of the total observed benefit would be attributable to prevention of pneumococcal meningitis. To our knowledge, this is the first study to estimate the potential impact on rates of IPD from accelerating administration of the first dose of pneumococcal conjugate vaccine to the youngest approved age of vaccination.

Studies on PCV7 efficacy and effectiveness vary by the match between vaccine serotypes and predominant IPD serotypes. Overall vaccine effectiveness for PCV7 vaccine serotypes is 81% to 97%, and vaccine effectiveness varies for each vaccine serotype (84% to 100%).^16,17 For IPD caused by vaccine serotypes, a subgroup analysis has shown higher vaccine effectiveness among previously healthy children (96%) than those with coexisting medical problems (81%).¹⁷

Vaccine efficacy and effectiveness in these studies varied, depending on the study population and time relative to PCV7 introduction. Prior to widespread PCV7 introduction (1995–1999), the randomized, double-blinded trial in Northern California Kaiser Permanente reported a 94% vaccine efficacy against all serotypes in the intent-to-treat analysis.¹⁶ However, in a prospective study between 1997–2000, the vaccine efficacy against all serotypes was much lower (46%-54%) for American Indian children 6 weeks to 24 months of age.²⁴ After the introduction of PCV7 (2001–2004), another study reported vaccine effectiveness against all serotypes of 72% (95% CI 65%-78%) among children younger than 2 years.¹⁷ They reported that the effectiveness of PCV7 decreased over time with observed changes in serotype distribution among cases of IPD; the overall vaccine effectiveness decreased from 80% in 2001 when vaccine serotypes accounted for 61% of IPD cases to 61% in 2002–2004 when vaccine serotypes accounted for 32% of IPD cases. Although vaccine effectiveness for serotypes included in the PCV7 remains high in most populations, the declining overall effectiveness reflects the emergence of non-PCV7 serotypes.

An observation underscoring the importance of new vaccine development is that the proportion of IPD cases caused by non-PCV7 serotypes and the incidence of IPD due to non-PCV7 serotypes have increased.^1–8 IPD attributable to non-PCV7 serotypes have increased significantly among children <1 year and 4 years of age from the pre-PCV7 era (1998–1999) to 2005; the largest increase in IPD due to non-PCV7 serotypes was 40% among children <1 year of age.⁸ New pneumococcal conjugate vaccines that include emerging non-PCV7 serotypes are now in development, including 9-valent (Wyeth, Madison, NJ), 10-valent (GlaxoSmithKline, London, United Kingdom), 11-valent (Aventis Pasteur, Lyon, France and GlaxoSmithKline, London, United Kingdom) and 13-valent (Wyeth, Madison, NJ)^18,25–29 Vaccines based on non-serotype-specific proteins are also being studied.²⁹

Our study showed that a decrease in IPD in young infants is possible if the first pneumococcal conjugate vaccine dose is accelerated to 6 weeks of age, in the context of a newly introduced childhood vaccine prior to the onset of indirect protection. In anticipation of a new pneumococcal conjugate vaccine, these results may be important, particularly for populations with high rates of IPD (such as Alaska natives,³⁰ Apache children,³¹ and children residing in Utah³²). Administration of the first pneumococcal conjugate vaccine dose at 6 weeks of age, which is permitted by the current ACIP guidelines, would require a change in routine practice patterns for many providers. Because all other vaccines routinely given at the 2-month visit can also be given at 6 weeks of age, an additional visit would not be necessary to institute this practice.³³

An important caveat is that administration vaccines at 6 weeks instead of 8 weeks of age could lead to increased numbers of health care visits, tests, or hospitalizations, or a missed significant infection, among infants who develop signs and symptoms, such as fever or fussiness, in the days after vaccination. Although evaluations for sepsis and meningitis based on such signs and symptoms in this age group are common, wide variations in clinical practice make it difficult to predict this potential impact.^34–36

This study has several limitations. First, PCV7 introduction provided indirect protection to infants too young to receive the first dose of the vaccine.¹² In our study, the calculated decrease in IPD rates accounts only for direct protection from the vaccine. Once such vaccines are in widespread use, indirect (herd) protection would likely alter the benefits of accelerated immunization. Further, our study does not estimate potential benefit of acceleration of the delivery of the second and third PCV7 vaccine doses, which is also permitted by current ACIP guidelines. In addition, we assumed a similar vaccine response to PCV7 in infants at 6 and 8 weeks of age, but we could not find any data comparing vaccine responses between infants of these age groups. However, the immunogenicity, efficacy, and safety of PCV7 in preterm and low-birth-weight infants have been shown to be similar to that in full-term and normal birth weight infants.³⁷ Finally, annual variation in IPD is known to occur, so the average anticipated impact is shown in our calculations. The observed impact of first dose acceleration may be higher or lower than our estimates, depending on the IPD burden and the degree to which the vaccine matches the prevalent strains in a region in a given year.

Another factor potentially affecting our estimates is the geographic and temporal overlap between the Northern California Kaiser Permanente PCV7 clinical trial and the Active Bacterial Core surveillance of the Emerging Infections Program Network for IPD, which were both conducted in San Francisco County between 1997 and 2000. Yet, San Francisco County accounted for 3% of the observed infant population under surveillance, so this overlap likely had minimal, if any, effect on our estimates.

Our findings suggest that acceleration of the administration of the first dose of pneumococcal conjugate vaccine from 2 months to 6 weeks of age could reduce the burden of IPD in young infants at the time of introduction of a new vaccine. Acceleration of the first dose of pneumococcal conjugate vaccine would require modification of vaccine administration practice, but this factor does not have to increase the number of routine health care visits, since all 2-month vaccines can be administered at 6 weeks.³³ Such a minor change in clinical practice could have significant benefit in reducing disease burden when a new pneumococcal vaccine is introduced, especially in regions where IPD rates are high.

Abbreviations

IPD

Invasive pneumococcal disease

PCV7

heptavalent pneumococcal conjugate vaccine

U.S.

United States

ACIP

Advisory Committee on Immunization Practices